Cases of poliomyelitis have been reported in the Philippines 19 years after the country was declared free of the disease. The return of poliomyelitis to the country emphasizes the need to maintain high levels of immunization while polioviruses continue to circulate.
A test of the poliovirus endgame
The global withdrawal of the Sabin type 2 poliovirus vaccine is a test of the feasibility of the plan, declared by the World Health Assembly in 1988, to eradicate all polioviruses.
Three countries endemic for poliovirus
I cannot let September pass without noting that 34 years ago this month, I arrived at Columbia University to start my laboratory toÂ do research on poliovirus (pictured). That virus is no longer the sole object of our attention – we are wrapping up some work on poliovirus andÂ our attention has shifted elsewhere. But this is a good month to think about the status of the poliovirus eradication effort.
So far this year 26Â cases of poliomyelitis have been recorded – 23 caused by wild type virus, and three caused by vaccine-derived virus. At the same time in 2015Â there wereÂ 44 reported cases of polio – smallÂ progress, but, in the words of Bill Gates, the last one percent isÂ the hardest.
One of the disappointmentsÂ this year is Nigeria. It was on the verge of being polio-free for one year – the last case of type 1 poliovirus in Nigeria had beenÂ recorded in July of 2014. In AugustÂ the government reported that 2 children developed polio in the Borno State. The genome sequence of the virus revealed that it had been circulating undetected in this region since 2011.Â Due to threats from militant extremists, it has not been possible for vaccination teams to properly cover this area, and surveillance for polioviruses has also been inefficient. The virus can circulate freely in a poorly immunized population, and as only 1% of infections lead to paralysis, cases of polio might have been missed.
The conclusion from this incident is thatÂ the declaration that poliovirus is no longer present in any region is only as good as the surveillance for the virus, which can never be perfect as all sources of infection cannot be covered.
Of the 26 cases of polio recorded so far in 2016, most have been in Afghanistan and Pakistan (9 and 14, respectively). It is quite clear that conflict has prevented vaccination teams from immunizing the population: in Pakistan, militants haveÂ attacked polio teams during vaccinationÂ campaigns.
Recently 5 of 27 sewageÂ samples taken from different parts of the province of Balochistan in Pakistan have tested positive for poliovirus. Nucleotide sequence analysis revealed that the viruses originated in Afghanistan. The fact that such viruses are present in sewage means that there are still individuals without intestinal immunity to poliovirus in these regions. In response to this finding, a massive polio immunization campaign was planned for the end of September in Pakistan. This effort would involve 6000 teams to reach 2.4 million children. Apparently police will be deployed to protect immunization teams (source: ProMedMail).
The success of the polio eradication program so far has made it clear that if vaccines can be deployed, circulation of the virus can be curtailed. If immunization could proceed unfettered, I suspect the virus would be gone in five years. But can anyone predictÂ whether it will be possible to curtail the violence in Pakistan, Afghanistan, and Nigeria that has limited polio vaccination efforts?
The switch from trivalent to bivalent oral poliovirus vaccine: Will it lead to polio?
In four months, 155 countries will together switch from using trivalent to bivalent oral poliovirus vaccine. Will this changeÂ lead to more cases of poliomyelitis?
There are three serotypes of poliovirus, each of which can cause paralytic poliomyelitis. The Sabin oral poliovirus vaccine (OPV), which has been used globally by WHO in the eradication effort, is a trivalent vaccine that contains all three serotypes.
In September 2015 WHO declared that wild poliovirus type 2 has been eradicated from the planet – no cases caused by this serotype had been detected since November 1999. However, in 2015, there were 9 cases of poliomyelitis caused by the type 2 vaccine. For theseÂ reasons WHO decided to removeÂ the type 2 Sabin strain fromÂ OPV, and switch from trivalent to bivalent vaccine in April 2016.
AfterÂ OPV is ingested, the viruses replicate in the intestinal tract, providing immunity to subsequent infection. During replication in the intestine, the vaccine viruses lose the mutations that prevent themÂ from causing paralysis. Everyone who receives OPV sheds these revertant viruses in the feces. In rareÂ cases (about one in 1.5 million) the revertant virusesÂ cause poliomyelitis in the vaccine recipient (these cases are called VAPP for vaccine-associated paralytic poliomyelitis). Vaccine-derived polioviruses can also circulate in the human population, and in under-vaccinated populations, they can cause poliomyelitis.
There were 26 reported cases of poliomyelitis caused by the type 1 or type 2 vaccine viruses in 2015. Nine cases of type 2 vaccine-associated polio were detected in four countries: Pakistan, Guinea, Lao Peopleâ€™s Democratic Republic, and Myanmar. RemovingÂ theÂ type 2 strain fromÂ OPVÂ will eliminateÂ vaccine-associated poliomyelitis in recipients caused by this serotype. WhenÂ the US switched from OPV to the inactivated poliovaccine (IPV) in 2000, VAPP was eliminated.
The problem with the trivalent to bivalent switch is thatÂ vaccine-derived type 2 poliovirus is likelyÂ still circulating somewhere on Earth.Â The last two reported cases of type 2 vaccine-associated polio in 2015 wereÂ reportedÂ in Myanmar in October. The viruses isolated from these cases were genetically related to strains that had been circulating in the same village in April of the thatÂ year. In other words, type 2 vaccine-derived strains have been circulating for an extended period of time in Myanmar; they have been known to persist for years elsewhere. If these virusesÂ continue to circulate past the time that immunization against type 2 virus stops, they could pose a threat to the growing numbers of infants and children who have not been immunized against this serotype.
Eventually as type 3, and then type 1 polioviruses are eradicated, it will also be necessary to stop immunizing with the respective Sabin vaccine strains. The switch from trivalent to bivalent vaccine in April 2016 is essentially an experiment to determineÂ if it is possible to stop immunizing with OPV without placing newborns at risk fromÂ circulating vaccine-derived strains.
Over 18 years ago Alan Dove and I argued that the presence of circulating vaccine-derived polioviruses made stopping immunization with OPVÂ a bad idea. We suggested instead aÂ switch from OPV to IPV until circulating vaccine-derived viruses disappeared. At the time, WHO disagreeed, but now they recommend that all countries deliver at least one dose of IPV as part of their immunization program. Instead of simply removing the Sabin type 2 strain from the immunization programs of 155 countries, it should be replaced with the inactivated type 2 vaccine. ThisÂ change would maintain immunity to this virus in children born after April 2016. Such aÂ synchronized replacementÂ is currently not in the WHO’s polio eradication plans. I hope that their strategy is the right one.
TWiV 371: Sympathy for the devil
On episode #371 of the science show This Week in Virology, the TWiVologistsÂ discuss the finding of a second transmissible cancer in Tasmanian devils, and development of new poliovirus strains for the production of inactivated vaccine in the post-eradication era.
You can find TWiV #371 at www.microbe.tv/twiv.
Virologists, start your poliovirus destruction!
I have worked on poliovirus for over thirty-six years, first as a posdoctoral fellow with David Baltimore in 1979, and then in my laboratory at Columbia University. The end of that research commences this year with the destruction of my stocks of polioviruses.
In 2015 there were 70 reported cases of poliomyelitis caused by wild type 1 poliovirus, andÂ 26 cases of poliomyelitis caused by circulating vaccine derived polioviruses (cVDPV) types 1 and 2. The last case of type 2 poliovirus occurred in India in 1999, and the virus was declared eradicated in 2015. Consequently the World Health Organization has decidedÂ that all remaining stocks of wild type 2 poliovirus shouldÂ be destroyed by the end of 2015.
My laboratory has worked extensively with type 2 polioviruses. Before we produced transgenic mice susceptible to poliovirus, we had studied the Lansing strain of type 2 poliovirus because it had the unusualÂ ability to infect wild type mice (polioviruses normally only infect certain primates). We determined the nucleotide sequence of the viral genome, identified the capsid as a determinant of the ability of the virus to infect wild type mice, and showed that swapping an eight amino acid sequence ofÂ capsid protein VP1 from a type 1 strain with that from Lansing conferred the ability to infect non-transgenic mice. These findings indicate that the ability of the Lansing strain of poliovirus to infect mice is likely due to recognition by the viral capsid of a receptor in the mouse central nervous system. In the past year we took advantage of the ability to produce mouse neurons from stem cells to attempt to identify the murine cellular receptor for Lansing virus.
To prevent further cases of poliomyelitis caused by cVDPVs, WHO has decided that there will be a synchronized, global switch from trivalent OPV to bivalent OPV in April 2016. By July of 2016 all remaining stocks of the Sabin type 2 poliovirus strains, which are used to produce OPV, will also be destroyed.
No wild type 3 poliovirus has been detected since November 2012, and it is likely that this virus will be declared eradicated within the next several years. At that time we will have to destroy our stocks of type 3 poliovirus. That leaves wild poliovirus type 1, which circulates only in Pakistan and Afghanistan. Given the small number of cases of paralysis caused by this type, it is reasonable to believe that eradication will occur within the next five years. If this timeline is correct, it means that I will be destroying my last vials of poliovirus around 2020.
It is of course necessary to destroy stocks of wild and vaccine polioviruses to preventÂ reintroduction of the virus and the disease that it causes. The 1978 release of smallpox virus from a laboratory in the United Kingdom, which causedÂ one death, lead to requestsÂ for reducing the number of laboratories that retained the virus. Today there are justÂ two official repositories of smallpox virus in the United States and Russia.
It is rare forÂ an investigator to be told to destroy stocks of the virusÂ that is the subject of his or her research. Over the years we have published 81 papers on poliovirus replication, vaccines, and pathogenesis. While I realize that it is absolutely essential to stop working on this virus, I do so with a certain amount of sadness. What other emotion could I have forÂ a virus on which I have expended so much thought and effort?
Image:Â Poliovirus by Jason Roberts
Correction: The synchronized switch in April 2016 is from trivalent to bivalent OPV, not OPV to IPV. Consequently I have removed comments related to an OPV-IPV switch.